Full text
| |
| Author(s): |
Alberto Rolim Muro Martinez
Total Authors: 1
|
| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2019-02-08 |
| Examining board members: |
Marcondes Cavalcante Franca Junior;
Fernando Cendes;
Wilson Marques Junior;
Acary Souza Bulle Oliveira;
Osvaldo José Moreira do Nascimento
|
| Advisor: | Marcondes Cavalcante Franca Junior |
| Abstract | |
Sensory neuronopathies (SN) represent a disorder characterized by dorsal root ganglia damage. The emerging clinical picture is composed by sensory ataxia and multifocal non-length dependent sensory deficits. The identification of this pattern opens a window of opportunity for the recognition of possible underlying diseases. Moreover, frequent symptoms such as pain and those related to autonomic dysfunction have not been clinically nor neurophysiologically evaluated. Another milestone to be mentioned is the rarity of SN added to unusual signs such as pseudoathetosis and pseudoparesis that turn usual the diagnostic delay. Additionally, the lack of reliable instruments capable of measuring the disease progression makes impossible natural history studies and the design of clinical trials. Hence, our objectives were: 1.to investigate novel etiologies for SN using clinical immunology and molecular biology techniques; 2.to describe clinical, topographic and treatment response characteristics of SN-related pain; 3.to evaluate clinical and neurophysiological functioning of the autonomic nervous system in SN patients; 4.to assess diagnostic delay and misdiagnoses of SN and 5.design and validate a clinical instrument capable to measure sensory ataxia. A total of 61 SN patients were enrolled, and different proportions of this group were included in each study. Two patients with infectious diseases-related SN were described: the first one was the first description of Zika virus-related SN and the second one was also the first description of a patient with SN and spastic paraparesis related to the HTLV1 infection. Anti-FGFR3 antibodies tested positive in 38% (16/42) of the patients and likely explained the disease cause in a significant proportion of the "idiopathic cases" 37.5% (9/24). Five patients (7% - 5/70) were diagnosed with the SN-autoimmune hepatitis association. These patients had positive screening for anti-FGFR3 antibodies (3/5 - 60%) and had, characteristically, unresponsiveness to the immunosuppressive treatment regarding the neurological clinical picture, whereas the hepatic disease underwent remission. Exome sequencing through new generation technology was another effort towards the etiologic approach of NS. Twenty-two idiopathic SN patients were enrolled but none of them had a definite diagnosis. Four patients had heterozygote variants in genes related to sensory ataxias (CUBN, POLG, FXN e FLVCR1) what raises the hypothesis that these are predisposing genes for SN. Pain complaints were present in 75% of the SN patients in this cohort, and more than half of them had asymmetric and neuropathic characteristics. Only 19% of the treated patients reached satisfactory pain remission. Autonomic manifestations were even more prevalent. Indeed, axonal sudomotor reflex evaluation disclosed abnormal sweat volumes in 91% of the patients what represents a post-ganglionic sympathetic dysfunction. Parasympathetic dysfunction was also revealed by the abnormal cardiovagal tests observed during heart rate variability tests. Considering the diagnostic delay, the mean interval from disease onset to the correct diagnosis was 5.4±5.4 years. On average, each patient had 3.08±1.4 misdiagnoses after consulting 4,3 ± 2,4 specialists. At last, we have proposed a clinical instrument to evaluate SN patients. This 10-item scale had a standardized Cronbach's alpha of 0.83 and intraclass correlation coefficient for interrater and intrarater evaluations of 0.96 and 0.98 respectively (AU) | |
| FAPESP's process: | 13/26410-0 - Clinical, immunological and neurophysiological characterization of sensory neuronopathies |
| Grantee: | Alberto Rolim Muro Martinez |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |